B cell Non-Hodgkin's lymphoma (B NHL) affects 5-10% of people with HIV/AIDS, a rate approximately 1,000 times higher than that observed for HIV-negative individuals. Even as the incidence of Kaposi's sarcoma has declined in the U.S. and Europe, B NHL rates have remained high. We postulated that the elevated risk for B NHL reflects HIV-mediated depletion of Vg2/Vd2+ T cells which are important for tumor surveillance of B NHL. The Vg2/Vd2+ T cell population is depleted early during infection and is the only T cell receptor-specific defect common to all individuals with HIV disease. Cell loss is specific for a subset expressing the Vg2-Jg1.2 chain, the same T cell receptor chain needed for recognition of B NHL. The Vg2/Vd2 T cells have strong proliferative responses to B NHL and are potently cytotoxic for tumor cells. However, there is no clear understanding of the mechanism for tumor recognition by Vg2/Vd2 T cells, the tumor effector phenotype remains undefined, and we are limited in our ability to assess the effects of therapy on this important component of tumor immunity. We study the roles for gamma/delta T cell receptor, NK receptors, and Toll-like receptors in B NHL recognition. In particular, we are interested in the recognition of tumor cell HSP60 that is required for Vg2/Vd2 T cell responses. We know from other systems, that HSP60 leader peptide blocks the recognition of HLA-E by the inhibitory receptor NKG2A and this might occur for Vg2/Vd2 T cells. We postulate that an additional pathway involving TLR2 binding to tumor cell HSP60, is needed to explain the data on anti-HSP60 antibody inhibition of tumor responses. Our experimental plan will define the tumor-specific T cell receptor, evaluate the roles for NK receptors and TLR, and utilize these insights to study tumor effector T cells in PBMC from patients with HIV infection that are undergoing long-term HAART. It is important to understand HIV-related defects in tumor immunity that contribute to rising B NHL rates. Assays for Vg2/Vd2 T cells might constitute new biomarkers for B NHL risk during HIV disease. In addition, several efforts are underway to exploit the potential of Vg2/Vd2 T cells for tumor cytotoxicity, by administering already approved and experimental drugs that increase cell counts and activity in vivo. These approaches hold promise for better clinical management of AIDS-related B NHL, to benefit patients with HIV disease.